Carlos A Ramos1,2, Natalie S Grover3,4, Anne W Beaven3,4, Premal D Lulla1,2, Meng-Fen Wu1,5, Anastasia Ivanova3,6, Tao Wang1,5, Thomas C Shea3,4, Cliona M Rooney1,7,8, Christopher Dittus3,4, Steven I Park3, Adrian P Gee1,7, Paul W Eldridge3, Kathryn L McKay3, Birju Mehta1, Catherine J Cheng3, Faith B Buchanan3, Bambi J Grilley1, Kaitlin Morrison3, Malcolm K Brenner1,2,7, Jonathan S Serody3,4,9, Gianpietro Dotti3,9, Helen E Heslop1,2,7, Barbara Savoldo3,9,10. 1. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital; Dan L. Duncan Cancer, Baylor College of Medicine; Houston, TX. 2. Department of Medicine, Baylor College of Medicine, Houston, TX. 3. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC. 4. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC. 5. Biostatistics Shared Resource, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX. 6. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC. 7. Department of Pediatrics, Baylor College of Medicine, Houston, TX. 8. Department of Pathology and Immunology, and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX. 9. Department of Immunology and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, NC. 10. Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Abstract
PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL). METHODS: We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety. RESULTS: Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent. CONCLUSION: Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.
PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL). METHODS: We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety. RESULTS: Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent. CONCLUSION: Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.
Authors: Shannon L Maude; Noelle Frey; Pamela A Shaw; Richard Aplenc; David M Barrett; Nancy J Bunin; Anne Chew; Vanessa E Gonzalez; Zhaohui Zheng; Simon F Lacey; Yolanda D Mahnke; Jan J Melenhorst; Susan R Rheingold; Angela Shen; David T Teachey; Bruce L Levine; Carl H June; David L Porter; Stephan A Grupp Journal: N Engl J Med Date: 2014-10-16 Impact factor: 91.245
Authors: A Guidetti; A Mazzocchi; R Miceli; E Paterno'; F Taverna; F Spina; F Crippa; L Farina; P Corradini; A M Gianni; S Viviani Journal: Leuk Res Date: 2017-09-25 Impact factor: 3.156
Authors: Stephen J Schuster; Jakub Svoboda; Elise A Chong; Sunita D Nasta; Anthony R Mato; Özlem Anak; Jennifer L Brogdon; Iulian Pruteanu-Malinici; Vijay Bhoj; Daniel Landsburg; Mariusz Wasik; Bruce L Levine; Simon F Lacey; Jan J Melenhorst; David L Porter; Carl H June Journal: N Engl J Med Date: 2017-12-10 Impact factor: 91.245
Authors: Bruce D Cheson; Richard I Fisher; Sally F Barrington; Franco Cavalli; Lawrence H Schwartz; Emanuele Zucca; T Andrew Lister Journal: J Clin Oncol Date: 2014-09-20 Impact factor: 44.544
Authors: Alison J Moskowitz; Paul A Hamlin; Miguel-Angel Perales; John Gerecitano; Steven M Horwitz; Matthew J Matasar; Ariela Noy; Maria Lia Palomba; Carol S Portlock; David J Straus; Tricia Graustein; Andrew D Zelenetz; Craig H Moskowitz Journal: J Clin Oncol Date: 2012-12-17 Impact factor: 44.544
Authors: Catherine M Bollard; Stephen Gottschalk; Vicky Torrano; Oumar Diouf; Stephanie Ku; Yasmin Hazrat; George Carrum; Carlos Ramos; Luis Fayad; Elizabeth J Shpall; Barbara Pro; Hao Liu; Meng-Fen Wu; Daniel Lee; Andrea M Sheehan; Youli Zu; Adrian P Gee; Malcolm K Brenner; Helen E Heslop; Cliona M Rooney Journal: J Clin Oncol Date: 2013-12-16 Impact factor: 44.544
Authors: Ingrid Glimelius; Sara Ekberg; Mats Jerkeman; Ellen T Chang; Magnus Björkholm; Therese M L Andersson; Karin E Smedby; Sandra Eloranta Journal: Am J Hematol Date: 2015-10-06 Impact factor: 10.047
Authors: Catherine M Bollard; Tamara Tripic; Conrad Russell Cruz; Gianpietro Dotti; Stephen Gottschalk; Vicky Torrano; Olga Dakhova; George Carrum; Carlos A Ramos; Hao Liu; Meng-Fen Wu; Andrea N Marcogliese; Cecilia Barese; Youli Zu; Daniel Y Lee; Owen O'Connor; Adrian P Gee; Malcolm K Brenner; Helen E Heslop; Cliona M Rooney Journal: J Clin Oncol Date: 2018-01-09 Impact factor: 50.717
Authors: Philippe Armand; Andreas Engert; Anas Younes; Michelle Fanale; Armando Santoro; Pier Luigi Zinzani; John M Timmerman; Graham P Collins; Radhakrishnan Ramchandren; Jonathon B Cohen; Jan Paul De Boer; John Kuruvilla; Kerry J Savage; Marek Trneny; Margaret A Shipp; Kazunobu Kato; Anne Sumbul; Benedetto Farsaci; Stephen M Ansell Journal: J Clin Oncol Date: 2018-03-27 Impact factor: 44.544
Authors: Spyridoula Vasileiou; Premal D Lulla; Ifigeneia Tzannou; Ayumi Watanabe; Manik Kuvalekar; Wendy L Callejas; Mrinalini Bilgi; Tao Wang; Mengfen J Wu; Rammurti Kamble; Carlos A Ramos; Rayne H Rouce; Zihua Zeng; Adrian P Gee; Bambi J Grilley; Juan F Vera; Catherine M Bollard; Malcolm K Brenner; Helen E Heslop; Cliona M Rooney; Ann M Leen; George Carrum Journal: J Clin Oncol Date: 2021-01-28 Impact factor: 44.544
Authors: Mohamed Abou-El-Enein; Magdi Elsallab; Gerhard Bauer; Barbara Savoldo; Steven A Feldman; Andrew D Fesnak; Helen E Heslop; Peter Marks; Brian G Till Journal: Blood Cancer Discov Date: 2021-08-03